Regulation of neurotransmitter secretion by Sphingosine-1-Phosphate
Neuronal activity greatly infl uences the formation and stabilization of synapses. Although receptors for sphingosine-1-phosphate (S1P), a lipid mediator regulating diverse cellular processes, are abundant in CNS, neuron-specifi c functions of S1P remain largely undefi ned. Here we present novel actions of S1P using primary hippocampal neurons as a model system, i.e. S1P triggers neurotransmitter secretion in a depolarization-independent manner. Sphingosine kinase 1 (SK1), a key enzyme for S1P production, was enriched in functional puncta of hippocampal neurons. Silencing SK1 expression by siRNA resulted in strong inhibition of depolarization-evoked glutamate secretion. FRET analysis demonstrated that S1P1 receptor at the puncta was activated during depolarization and that depolarizationinduced S1P1 receptor activation was inhibited in SK1-knockdown cells. Importantly, exogenously added S1P at nanomolar concentration by itself elicited glutamate secretion from hippocampal cells even when Na+ -channel was blocked by tetrodotoxin, suggesting that S1P acts on presynaptic membranes. These fi ndings indicate that S1P, through its autocrine action, facilitates spontaneous glutamate secretion. We are now confi rming these fi ndings using electrophysiological approaches and also studying the role of S1P in memory formation and learning using knockout mice.